Project Summary The most recent outbreak of Zika Virus (ZIKV) in Brazil has presented with unexpectedly severe neurological manifestations, which were not observed in prior outbreaks of ZIKV or other related flaviviruses. This prompted the WHO to declare a public health emergency of international In addition to neurologic disorders, ZIKV infection is now being increasingly associated with ocular complications such as uveitis, acute maculopathy, pigmentory retinopathy, and chorioretinal atrophy. These clinical findings make it clear that macular and chorioretinal disease can significantly impact visual outcomes in ZIKV-infected infants and adults. However, it is not yet clear whether congenital ocular complications are directly caused by ZIKV or are secondary to microcephaly. As the retina is the primary target of ZIKV in the eye, we have developed a mouse model of ZIKV-induced chorioretinal atrophy. We found that cells lining the blood-retinal barrier (BRB), the retinal pigment epithelium (RPE), are highly permissive to ZIKV. Collectively, these findings led us to postulate that ZIKV gains access to the eye by via BRB. Despite the close relationship between ZIKV and other members of the flaviviridae family, such as DENV, WNV, and JEV, it remains unclear why only ZIKV causes congenital disorders and associated complications. To address this question , we compared the transcriptome of ZIKV-infected RPE cells with the transcriptome signatures of the other related viruses. This led to the identification of ABCG1, a cholesterol membrane transporter, as a candidate gene that is specifically involved in the pathogenesis of ZIKV. In support, our preliminary data show that pharmacological inhibition of ABCG1 activity attenuated ZIKV replication in RPE cells. Thus, the overall objective of this study concern. is to determine molecular mechanisms by which ABCG1 promotes viral replication in RPE and determine the consequences of ABCG1 ablation in the pathobiology of ZIKV-induced chorioretinal atrophy. To achieve this goal, we will pursue two specific aims: Aim-1 is to determine how ZIKV-induced ABCG1 expression modulates cholesterol synthesis/efflux to promote ZIKV replication in RPE cells. Aim-2 is designed to investigate the role of ABCG1 in the pathobiology of ZIKV-induced chorioretinal atrophy in ABCG1-BEST1Cre mice harboring an RPE-specific conditional knockout. Upon completion, these aims will elucidate the role of ABCG1 in ocular ZIKV infection, particularly in the pathogenesis of chorioretinal atrophy. Given the rapid spread of ZIKV and its impact on ocular health, this work is of paramount importance for the development of drugs to treat ZIKV infection and prevent its complications.